NCI study identifies essential genes for cancer immunotherapy

A new study identifies genes that are necessary in cancer cells for immunotherapy to work, addressing the problem of why some tumors don’t respond to immunotherapy or respond initially but then stop as tumor cells develop resistance to immunotherapy.

The study, from the National Cancer Institute (NCI), was led by Nicholas Restifo, M.D., a senior investigator with NCI’s Center for Cancer Research, with coauthors from NCI; Georgetown University, Washington D.C.; the Broad Institute of MIT and Harvard University, Cambridge, Massachusetts; New York University, New York City; and the University of Pennsylvania, Philadelphia. It was published online in Nature on August 7, 2017. NCI is part of the National Institutes of Health (NIH).

“There is a great deal of interest in cancer immunotherapy, especially for patients who have metastatic cancer,” said Dr. Restifo. “The response to immunotherapy can be fantastic, but understanding why some patients don’t respond will help us improve treatments for more patients.”

Cancer immunotherapy relies on T cells, a type of cell in the immune system, to destroy tumors. Dr. Restifo and his colleagues have previously shown that the infusion of large numbers of T cells can trigger complete regression of cancer in patients. They and others have also shown that T cells can directly recognize and kill tumor cells.

However, some tumor cells are resistant to the destruction unleashed by T cells. To investigate the basis for this resistance, the researchers sought to identify the genes in cancer cells that are necessary for them to be killed by T cells.

Working with a melanoma tumor cell line, the researchers used a gene editing technology called CRISPR that “knocks out,” or stops the expression, of individual genes in cancer cells. By knocking out every known protein-encoding gene in the human genome and then testing the ability of the gene-modified melanoma cells to respond to T cells, they found more than 100 genes that may play a role in facilitating tumor destruction by T cells.